Abstract
Squamous cell carcinoma–related oncogene (SCCRO, also known as DCUN1D1) is a component of the E3 for neddylation. As such, DCUN1D1 regulates the neddylation of cullin family members. Targeted inactivation of DCUN1D1 in mice results in male-specific infertility. Infertility in DCUN1D1-/- mice is secondary to primary defects in spermatogenesis. Time-dam experiments mapped the onset of the defect in spermatogenesis to 5.5 to 6 weeks of age, which temporally corresponds to defects in spermiogenesis. Although the first round of spermatogenesis progressed normally, the number of spermatozoa released into the seminiferous lumen and epididymis of DCUN1D1-/- mice was significantly reduced. Spermatozoa in DCUN1D1-/- mice had multiple abnormalities, including globozoospermia, macrocephaly, and multiple flagella. Many of the malformed spermatozoa in DCUN1D1-/- mice were multinucleated, with supernumerary and malpositioned centrioles, suggesting a defect in the resolution of intercellular bridges. The onset of the defect in spermatogenesis in DCUN1D1-/- mice corresponds to an increase in DCUN1D1 expression observed during normal spermatogenesis. Moreover, consistent with its known function as a component of the E3 in neddylation, the pattern of DCUN1D1 expression temporally correlates with an increase in the neddylated cullin fraction and stage-specific increases in the total ubiquitinated protein pool in wild-type mice. Levels of neddylated Cul3 were decreased in DCUN1D1-/- mice, and ubiquitinated proteins did not accumulate during the stages in which DCUN1D1 expression peaks during spermatogenesis in wild-type mice. Combined, these findings suggest that DCUN1D1-/- mice fail to release mature spermatozoa into the seminiferous lumen, possibly due to unresolved intercellular bridges. Furthermore, the effects of DCUN1D1 on spermatogenesis likely involve its regulation of cullin-RING-ligase (CRL)–type ubiquitin E3 activity during spermiogenesis through its role in promoting Cul3 neddylation. The specific CRLs required for spermiogenesis and their protein targets require identification.
Highlights
Cullin-RING–based E3 ubiquitin ligases (CRLs), the largest class of mammalian ubiquitination E3s [1], are specified by more than 600 human genes and are involved in the control of many cellular processes [2]
We showed that decreased cullin neddylation and CRL-promoted ubiquitination in DCUN1D1-/- mice temporally correlate with defective spermiogenesis
We have previously shown that proliferative activity is decreased in murine embryonic fibroblasts from DCUN1D1-/- mice, owing to defective cullin neddylation—this may be the cause of runting in these mice [10]
Summary
Cullin-RING–based E3 ubiquitin ligases (CRLs), the largest class of mammalian ubiquitination E3s [1], are specified by more than 600 human genes and are involved in the control of many cellular processes [2]. The assembly and activity of RING E3s are regulated in large part by neddylation, the posttranslational modification of cullins by Nedd8 [3]. Neddylation, a process analogous to ubiquitination in which a tripartite cascade results in covalent modification of the cullin family of proteins by the ubiquitin-like protein Nedd, is regulated by the activity of the E3 for neddylation [4,5,6]. Despite the critical importance of neddylation, the specifics of how this process is regulated and the CRLs and proteins affected by it remain poorly understood. Mutations in the core components of this pathway (including Roc, Cul, Cul, and Uba3) result in early embryonic lethality in mice [12,13,14,15,16], DCUN1D1-knockout mice are viable, likely owing to compensation from paralogs present exclusively in higher organisms [17]. Loss of DCUN1D1 in the testis results in male-specific infertility in DCUN1D1-/- mice
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